WO2016127812A1 - Dérivé de sparstolonin b, son procédé de préparation et son utilisation - Google Patents

Dérivé de sparstolonin b, son procédé de préparation et son utilisation Download PDF

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Publication number
WO2016127812A1
WO2016127812A1 PCT/CN2016/072416 CN2016072416W WO2016127812A1 WO 2016127812 A1 WO2016127812 A1 WO 2016127812A1 CN 2016072416 W CN2016072416 W CN 2016072416W WO 2016127812 A1 WO2016127812 A1 WO 2016127812A1
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WO
WIPO (PCT)
Prior art keywords
group
black
trilobide
dmso
hydrogen
Prior art date
Application number
PCT/CN2016/072416
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English (en)
Chinese (zh)
Inventor
孙健
王超
Original Assignee
中国科学院成都生物研究所
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Publication of WO2016127812A1 publication Critical patent/WO2016127812A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/06—Peri-condensed systems

Definitions

  • the invention belongs to the technical field of chemical and pharmaceutical inventions, and in particular relates to a black trilobide B derivative, a preparation method thereof and use thereof.
  • the black-triangular black-triangular plant Sparganium stoloniferum Buch-Ham tubers which are peeled and dried tubers are traditional Chinese medicine trigonal, taste spicy, bitter, flat, with sputum through, blood stasis, Gas elimination and other effects.
  • Liang Qiaoli et al found a new type of oxazolidine B (Sparstolonin B) in Sanling, and has anti-atherosclerosis effect (Chinese patent, CN101899054A), in-depth molecular biology Studies have shown that black trilobide B is a selective antagonist of TLR 2 and TLR 4 (Qiao li Liang et al, Jounal of biological chemistry, 286 (30), 26470-26479), with strong anti-inflammatory and immune Stimulation inhibition effect, can be used to reduce inflammation and reperfusion, tumor, chronic inflammatory bowel disease, diabetes, Alzheimer's disease, chronic obstructive pulmonary disease, sepsis, lupus erythematosus, rheumatoid arthritis and other inflammation Immune disease (Chinese patent, CN102218058A) is expected to develop into a new type of drug for inflammatory diseases.
  • Black trigonal lactone B has a low natural content, is difficult to extract and separate, and its source is greatly limited.
  • One of the objects of the present invention is to provide a black trilobide B derivative.
  • One of the objects of the present invention is to provide a process for preparing a black trilobide B derivative.
  • One of the objects of the present invention is to provide a use of a black trilobide B derivative.
  • the structure of the black trilobide B derivative of the present invention is as follows:
  • R is hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl, C 5-10 aryl, pyridyl, C n H 2n X, OR 1 or NR 2 R 3 , wherein n is 1 -6, X is a vinyl group, an ethynyl group, a C 5-10 aryl group, an aza heteroaryl group having 1 to 4 nitrogen atoms and 1 to 5 carbon atoms, a hydroxyl group, a C 1-4 alkoxy group, an amino group, N,N-bisC 1-4 alkylamino, carboxyl, amido, sulfonylamino, C 1-4 alkyloxycarbonyl, cyano or nitro, R 1 is hydrogen, C 1-4 alkyl, benzyl Or methoxybenzyl, R 2 and R 3 are each independently hydrogen, C 1-4 alkyl, benzyl, methoxybenzyl or R 2 , and R 3 and N atom together form a
  • the black trilobide B derivative described above is characterized in that n is 1-3, and X is a vinyl group, a phenyl group, a decyl group, a hydroxyl group, a t-butoxy group, an amino group, and N.
  • N-dimethylamino, pyrrolidinyl, carboxyl or amide group R 1 is hydrogen, methyl, isopropyl, tert-butyl, benzyl, and R 2 and R 3 are each hydrogen, methyl or R 2 R 3 and the N atom together form a 5 or 6 membered ring.
  • the black trilobide B derivative described above is characterized in that R is hydrogen, methyl, isopropyl, t-butyl, cyclopropyl, cyclopentyl, cyclohexyl, phenyl, Pyridyl, allyl, benzyl, fluorene methylene ethyl, hydroxy, hydroxyethyl, tert-butoxy, cyanoethyl, amino, aminopropyl, N,N-bismethylamino, pyrrolidinyl , piperidinyl.
  • the black trilobide B derivative of the present invention can be prepared by a simple method and is easily amplified, and the general preparation method is as follows:
  • black trilobide B is prepared by reacting 1-3 equivalents of a primary amine or a common salt thereof.
  • the black trilobide B derivative of the present invention can be used for the preparation of an antitumor drug.
  • theization in the present invention Compound 10, the structural formula is as follows:
  • the invention has the advantages that the compound of the invention has novel structure, has high activity of inhibiting tumor cell growth, has certain drug-forming properties, has the potential to develop into a novel drug, and has a simple preparation method and is easy to operate.
  • the 1,3-propanediamine (21 mg) was added to a solution of the black trilobide B (50 mg) in isopropanol, and the compound of Example 1 was obtained by the procedure of Example 1 to obtain 41 mg of Compound 14 as a pale yellow solid. .
  • N,N-dimethylglycolamide 38 mg was added to a solution of black trilobide B (50 mg) in isopropanol, and the compound of Example 21 was obtained by the method of Example 1, to obtain a pale yellow solid.
  • the rate is 84%.
  • the anticancer activities (IC 50 values) of the compounds listed in the specification were measured in human hepatoma cells HepG2, BEL-7402 and human cervical cancer Hela, respectively, using the CCK-8 method.
  • the cells in the logarithmic growth phase were inoculated into the 96-well cell culture plate at 5 ⁇ 10 3 cells/well, and 3 replicate wells were set.
  • Table 1 represents the activity test results of the compounds

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne un dérivé du produit naturel sparstolonin B et un procédé de préparation associé et son utilisation pour la préparation de médicaments antitumoraux. La formule développée du dérivé est la suivante, dans laquelle R représente hydrogène, C1-6-alkyle, C3-6-cycloalkyle, C5-10-aryle, pyridyle, CnH2nX, OR1 ou NR2R3 ; n vaut 1 à 6, X représente vinyle, acétényle, C5-10-aryle, azo-aryle comprenant 1 à 4 atomes d'azote et 1 à 5 atomes de carbone, hydroxyle, C1-4-alcoxyle, amino, N, N-bi(C1-4-alkylamino), carboxyle, acylamino, sulfonylamino, C1-4-alcoxycarbonyle, cyano ou nitrile ; R1 représente hydrogène, C1-4-alkyle, benzyle ou méthoxybenzyle ; et R2 et R3 représentent, respectivement, hydrogène, C1-4 alkyle, benzyle, méthoxybenzyle ou R2 et R3 forment ensemble un cycle à 4-7 chaînons avec des atomes de N. Le dérivé de sparstolonin B dans la présente invention est utilisé pour des médicaments antitumoraux et le composé dans la présente invention présente une nouvelle structure, présente une aptitude relativement bonne à la transformation en médicament et une activité relativement élevée d'inhibition de la croissance de cellules tumorales et présente un procédé de préparation simple et pratique et est facile à mettre en oeuvre et à amplifier.
PCT/CN2016/072416 2015-02-11 2016-01-28 Dérivé de sparstolonin b, son procédé de préparation et son utilisation WO2016127812A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN201510071922.6 2015-02-11
CN201510071922.6A CN104725389B (zh) 2015-02-11 2015-02-11 黑三棱内酯b衍生物及其制备方法和用途

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WO2016127812A1 true WO2016127812A1 (fr) 2016-08-18

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CN (1) CN104725389B (fr)
WO (1) WO2016127812A1 (fr)

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104725389B (zh) * 2015-02-11 2017-03-01 中国科学院成都生物研究所 黑三棱内酯b衍生物及其制备方法和用途
CN105949213B (zh) * 2016-06-22 2017-10-20 南京中医药大学 一种天然产物三棱内酯SsnB及其关键中间体的合成方法
CN106361745A (zh) * 2016-11-18 2017-02-01 南京中医药大学 三棱内酯B（Sparstolonin B）在制备抗肿瘤转移药物中的应用

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1277613A (zh) * 1997-09-03 2000-12-20 吉尔福特药品有限公司 聚(adp－核糖)聚合酶("parp")抑制剂、治疗神经系统或心血管组织损伤的方法和药物组合物
CN101899054A (zh) * 2009-06-25 2010-12-01 南京中医药大学 抗动脉粥样硬化的黑三棱内酯b化合物及其制备方法
CN102218058A (zh) * 2011-04-29 2011-10-19 南京中医药大学 黑三棱内酯b作为tlr2和tlr4拮抗剂在制药中的应用
CN103483348A (zh) * 2013-09-06 2014-01-01 中国科学院成都生物研究所 黑三棱内酯b及其关键中间体的合成
CN104725389A (zh) * 2015-02-11 2015-06-24 中国科学院成都生物研究所 黑三棱内酯b衍生物及其制备方法和用途
CN105147669A (zh) * 2015-07-16 2015-12-16 南京中医药大学 三棱双苯内酯和三棱双苯内酯b的衍生物在制备抗炎药物中的应用

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6291425B1 (en) * 1999-09-01 2001-09-18 Guilford Pharmaceuticals Inc. Compounds, methods and pharmaceutical compositions for treating cellular damage, such as neural or cardiovascular tissue damage

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1277613A (zh) * 1997-09-03 2000-12-20 吉尔福特药品有限公司 聚(adp－核糖)聚合酶("parp")抑制剂、治疗神经系统或心血管组织损伤的方法和药物组合物
CN101899054A (zh) * 2009-06-25 2010-12-01 南京中医药大学 抗动脉粥样硬化的黑三棱内酯b化合物及其制备方法
CN102218058A (zh) * 2011-04-29 2011-10-19 南京中医药大学 黑三棱内酯b作为tlr2和tlr4拮抗剂在制药中的应用
CN103483348A (zh) * 2013-09-06 2014-01-01 中国科学院成都生物研究所 黑三棱内酯b及其关键中间体的合成
CN104725389A (zh) * 2015-02-11 2015-06-24 中国科学院成都生物研究所 黑三棱内酯b衍生物及其制备方法和用途
CN105147669A (zh) * 2015-07-16 2015-12-16 南京中医药大学 三棱双苯内酯和三棱双苯内酯b的衍生物在制备抗炎药物中的应用

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CN104725389A (zh) 2015-06-24

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